SQ109 is a novel antitubercular drug with IC50 value of 0.2 μg/ml on XDR [1].
Tuberculosis is a serious infection disease caused by Mycobacterium tuberculosis (Mtb). It is the leading single-agent killer with highest fatality rate. About more than three million lives were killed by tuberculosis every year. Even so, the existed drugs for TB treatment are facing many challenges including the side effects and the development of multidrug-resistant tuberculosis (MDR-TB). As a novel antitubercular drug, SQ109 has a distinguished mechanism of action and improved potency. The target of it is the mycolic acid transporter MmpL3 required for the synthesis of mycolic acid in cell wall of Mtb [1 and 2]. ?
SQ109 was screened out from a big chemical library designed around the active pharmacophore of ethambutol (EMB). Even so, SQ109 had different chemical structure, potency and mechanism with EMB. Among the top 27 candidates, SQ109 showed the highest selectivity index value and lowest IC50 value in vitro of 16.7 and 0.78 μg/ml, respectively. SQ109 displayed potent activity against all the substrains of Mtb including XDR- and MDR-TB clinical strains with IC50 values of 0.2 μg/ml. Besides that, SQ109 also showed significant effects on other pathogenic Mycobacteria with MIC values in the range of 4 to 16 μg/ml [1].
SQ109 showed low oral bioavailability in PK studies. The carbamate prodrug of it with improved oral bioavailability (from 21.4% to 91.4 %) exerted a high tissue distribution in rats. In the infected mice, treatment of SQ109 at dose of 10 mg/kg significantly attenuated the symptom of weight loss. In the chronic TB model in mice, 10 mg/kg of SQ109 showed better potency than EMB at dose of 100 mg/kg. Besides that, it was reported that the combination treatment of SQ109 and bedaquiline demonstrated a durable cure in infected mice model [1 and 3].
参考文献:
[1] Sacksteder K A, Protopopova M, Barry C E, et al. Discovery and development of SQ109: a new antitubercular drug with a novel mechanism of action. Future microbiology, 2012, 7(7): 823-837.
[2] Meng Q, Luo H, Liu Y, et al. Synthesis and evaluation of carbamate prodrugs of SQ109 as antituberculosis agents. Bioorganic & medicinal chemistry letters, 2009, 19(10): 2808-2810.
[3] SQ109 (2008) SQ109. Tuberculosis (Edinb) 88, 159–161.
[4] Reddy V M, Dubuisson T, Einck L, et al. SQ109 and PNU-100480 interact to kill Mycobacterium tuberculosis in vitro. Journal of antimicrobial chemotherapy, 2012: dkr589.
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Cell experiment: |
The LLC-MK2 cells are treated with SQ109 (2.5 to 20 μM) and incubated for 96 h at 37°C. Fresh RPMI 1640 medium containing only 10% FBS is added to the untreated samples as a control. To determine toxicity, the MTS/PMS assay is performed. The selectivity index of SQ109 is determined based on its activities against the trypomastigote and intracellular amastigote forms of T.cruzi, calculated as the ratio of the 50% cytotoxic concentration (CC50) of mammalian cells to the IC50 or 50% lysing concentration (LC50) of T.cruzi. All experiments are performed in duplicate. The means are determined from ≥3 experiments[1]. |
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Animal experiment: |
Mice[2] Female C57BL/6 mice (8 weeks old) are used. Oral treatment of mice with INH (25 mg/kg), ethambutol (EMB) (100 mg/kg) and SQ109 (0.1, 10 and 25 mg/kg) is initiated 20 days after inoculation. Control groups of infected but untreated mice are killed at the initiation of therapy (early controls) or at the end of the treatment period. There are six mice per group. Chemotherapy is given daily for 5 days per week until the mice are killed, 4 weeks after initiation of treatment. The spleen and lungs are aseptically removed and weighed. The organs are homogenized in 2 ml of sterile PBS containing 0.05% Tween-80. Homogenate samples from individual tissues are diluted 10-fold in PBS and plated on 7H10 agar dishes. Inoculated dishes are incubated at 37°C in ambient air for 3 weeks prior to calculation of CFU. Viable counts are converted to a logarithmic scale; readings are corrected to represent whole organ totals. The severity of infection and the effectiveness of the treatments are assessed by the survival rate, and the mean number of CFU in mouse organs. Rats and Dogs[3] Male Fischer rats (271-289 g) and beagle dogs (7.5-8.9 kg, two males and two females per dose group) are used. Rats are given either a single intravenous (i.v.) bolus dose of 1.5 mg/kg (9 mg/m2) or an oral dose of 13 mg/kg (78 mg/m2) of SQ109 (n=8 per dose group); rats are divided into subgroups consisting of four rats per subgroup. Rat blood (0.7 mL) is withdrawn from the jugular vein catheter at alternating time points from individual rats in each subgroup. Blood samples are collected at 2, 5, 10, 15 and 30 min and 1, 3, 6, 10 and 24 h after a single i.v. administration, or 5, 15 and 30 min and 1, 2, 4, 6, 10 and 24 h after a single oral administration. Each blood sample is centrifuged to separate plasma, which is then stored at ?70°C until analysis. Beagle dogs are dosed by gavage at either 3.75 or 15 mg/kg (75 or 300 mg/m2), or intravenously at either 0.45 or 4.5 mg/kg (9 and 90 mg/m2). Dog blood (0.7 mL) is withdrawn from the jugular vein at 2, 5, 10, 20 and 30 min and 1, 2, 4, 8, 12, 18 and 24 h after a single i.v. administration, or 10, 20 and 30 min and 1, 2, 4, 8, 12, 18 and 24 h after a single oral administration. |
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参考文献: [1]. Veiga-Santos P, et al. SQ109, a new drug lead for Chagas disease. Antimicrob Agents Chemother. 2015 Apr;59(4):1950-61. |
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